The worst outbreak of Ebola in recorded history is currently raging in West Africa and has touched our shores. Despite considerable effort from NGOs, international agencies, and national governments, we have not stemmed the tide of the epidemic. An absence of approved vaccines and drugs has compounded the significant social, political, and infrastructure issues that have stymied the response. The goal of this project is to build on our extensive body of work and develop a combination of approved drugs to repurpose to combat Ebola. We seek a practical drug for use by patients, as well as (prophylactically) by family, medical, and community contacts: one that is relatively inexpensive, shelf-ready, easy to transport and deliver (i.e., without a cold chain), and orally-available. The starting point for ou project was a screen of 1800 FDA approved small molecular weight compounds. From these, we identified 105 approved drugs that strongly inhibit Ebola infections in cell cultures. We next characterized the 30 top hits as to whether they block the entry or a post- entry stage of Ebola infection. In concurrent work we found that several pairs of these drugs show synergistic anti-Ebola activity (in cell cultures). The hypothesis for this proposal is, therefore, that we can develop a cocktail of orally-available approved drugs that potently impedes Ebola. The project has three Specific Aims: (1) identify combinations of two entry inhibitors that strongly block Ebola (in cell cultures); (2) identify combinations of entry + post-entry inhibitors that strongly block Ebola (in cell cultures); and (3) test the best pairs in the mouse model of lethal Ebola infection. The next phase would be to test the most promising pair in non-human primates. The long-term goal is to repurpose a cocktail of approved drugs to treat Ebola patients and patient contacts. We have assembled a superb team to carry out the work, with members and collaborators from academic, government, and a small pharmaceutical lab. We have also enlisted an expert molecular pharmacologist and an expert clinical virologist to help guide our work. The project will use state-of- the-art assays, equipment, and facilities at all stages, including ones at the NIAID Integrated Research Facility and the NIH National Center for Advancing Translational Sciences. Our project builds on strong preliminary data supporting the development of a cocktail of approved drugs to treat Ebola. It is innovative in that it combines three key concepts in modern anti-viral pharmacology: (i) repurposing approved drugs; (ii) developing drug combinations, and (iii) targeting host cell pathways. The immediate significance of our work is to the urgent need to develop practical drugs to combat Ebola. The longer significance is to the general mission of repurposing combinations of approved drugs to treat other rare, but highly lethal, emerging viral infections.